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It is our responsibility as pediatric health care providers to promote the health and well-being of the children who present to us for care. We respectfully disagree with Crowe et al that, "[t]here is simply no firm evidence that children will live longer when medicated earlier with AIDS drugs." On the contrary, there is ample evidence that highly active antiretroviral therapy (HAART) has had tremendous effects on improving morbidity profiles, reducing mortality rates, and delaying death among HIV-infected children.1,2 Regarding infants in particular, analyses from a large prospective study of 360 HIV-infected US children (Perinatal AIDS Collaborative Transmission Study) showed that infants who received early treatment with HAART were significantly less likely to progress to AIDS or death compared with those who received no therapy, adjusting for year of birth and maternal disease factors.3 The increased potency of regimens containing protease inhibitor (PI) drugs has resulted in enhanced survival of HIV-infected children and a reduction in opportunistic infections and other complications of HIV infection as demonstrated in a prospective longitudinal cohort study (Perinatal AIDS Collaborative Transmission Group, PACTG 219),4 which started enrollment before the availability of PI therapy. The increased use of PI-containing therapy (from 0% before 1996 to >70% by 1998) was accompanied by a substantial decrease in mortality: mortality decreased from 5% in 1995/1996 to only 1% in 1997/1998. Similar reductions in mortality with introduction of HAART in HIV-infected children in Europe have also been reported.2,5,6
Crowe et al suggest that because children face a greater number of years on therapy than adults, a rational approach is to delay the initiation of therapy as long as possible. We agree with this approach as long as the child's clinical, immunologic, or HIV RNA status does not place them in a category at risk for rapid disease progression as outlined by national and international guidelines.7 For all the pediatric HIV patients in our clinic, we followed the expert guidelines when recommending institution of antiretroviral therapy. The working group recommends initiation of therapy for infants <12 months of age who have clinical or immunologic symptoms of HIV disease regardless of HIV RNA levels and consideration of therapy for HIV-infected infants <12 months old who are asymptomatic and have normal immune parameters. Because the risk of disease progression slows in children older than 1 year, the option of deferring treatment can be considered for older children without clinical symptoms, and even in those with mild-moderate clinical symptoms or immune suppression, when plasma HIV RNA levels are 
100000 copies per mL.7 Studies have shown that children older than 1 year of age with HIV RNA levels of >100000 copies per mL are at high risk for mortality.8,9
The potential adverse effects of HAART are not benign, as referenced in our original article10–13 and in the letter by Crowe et al.14–16 However, a recent study that examined quality of life (QOL) among 940 school-aged children with perinatally acquired HIV infection compared QOL outcomes between treatment groups that differed according to the use of PI combination therapy. Although receipt of PI therapy was associated with an increased rate of diarrhea (28 vs 13%; adjusted odds ratio: 2.59; 95% confidence interval: 1.74–3.85), the study found no evidence of direct negative effects of PI therapy on QOL outcomes other than the increased rate of diarrhea. In fact, better health perceptions and physical functioning scores were associated with log10 CD4+ cell counts and height z scores, respectively, both of which were improved by PI therapy. Thus, the effects of PI combination therapies to slow or prevent disease progression and increase CD4+ cell counts and height growth have the potential to improve QOL among children with HIV infection.17 Treatment recommendations recently updated by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children support an opinion that the potential benefits of HAART outweigh the potential adverse effects.7
In the children of our cohort who we perceived to be experiencing therapy failure (persistently high viral loads and falling CD4+ T cell percentages), we did not suspect lack of adherence as the cause of treatment failure until viral-resistance testing became available. The caregivers of these patients always indicated that they were adherent with the prescribed regimen. As new antiretroviral agents became available over the years, we tried multiple regimens in these children to hopefully overcome what we perceived as failure resulting from viral resistance, poor bioavailability, or a combination thereof. However, once in vitro testing allowed us to rule out resistance as a cause for failure, we became suspicious of nonadherence and began using directly observed therapy (DOT) to exclude inadequate bioavailability of the drug as a cause for treatment failure. Thus, Crowe et al are correct in their statement that we relied heavily on high viral load to determine lack of adherence, but this was not until we excluded other potential causes of treatment failure.
The supposition that some of the patients were being rigorously medicated at home and their viral load remained high for other reasons is highly unlikely given that viral genotype and/or phenotype findings indicated viral sensitivity to the patient's medication regimen, and DOT in the hospital for 4 days with the same regimen resulted in a significant decrease in the patient's viral load in the absence of observed adverse effects.18 The primary caregivers of the 2 patients who were eventually placed in foster care did not express an opinion that HAART would not benefit their child or that it caused adverse effects or was difficult to administer. When patient 3 was 2.5 years of age, a gastrostomy tube was placed to enhance ease of drug administration. In patient 4, foster care placement occurred a second time after a brief stay with the mother resulted in a rapid rebound of the patient's viral load. The drug regimen consisted of 1 Trizivir tablet by mouth twice daily, which the patient took without difficulty while in foster care, and resulted in HIV RNA levels below detection while the child was in foster care.
We differ with the opinion of Crowe et al that the interventions provided to these children were without evidence of benefit. At the time that reports of medical neglect were made on behalf of patients 3 and 4, these children were at high risk for disease progression as indicated not only by their high viral loads but also by their extremely low CD4+ T cell percentages (0% and 4%, respectively). Based on data from the HIV Pediatric Prognostic Markers Collaborative Study Group, patient 3 had a 20% estimated probability of death and a 40% estimated probability of developing AIDS within 12 months in the absence of antiretroviral therapy.19 Patient 4 had a 10% estimated probability of death and a 25% estimated probability of developing AIDS within 12 months in the absence of antiretroviral therapy.19 Patient 4 had a history of 2 hospitalizations for bacteremia caused by Streptococcus pneumoniae, 1 associated with severe periorbital cellulitis, and 2 hospitalizations for varicella zoster before foster care placement. This patient has not been hospitalized because of medical illness since foster care placement 6 years ago. Because the primary caregivers of these 2 children refused to be responsible for delivering therapy, we feel that the interventions we undertook, which eventually resulted in foster care placement by court authorities, were and remain in the best interests of these children. Patients 3 and 4 have remained alive and asymptomatic since their placement in foster care 3 and 6 years ago, respectively.
Crowe et al are incorrect in their statement that we did not acknowledge the difficult social circumstances of the caregivers. In our clinic, a pediatric social worker visits with each family at every visit to provide education and works with local agencies to provide assistance in identified areas of need including individual and family psychological counseling and financial-assistance programs. As discussed in our original article, multiple strategies including repeated counseling by multiple experts (physicians, nurses, pharmacologists, and social workers) in pediatric HIV treatment are used to encourage adherence among the patients and their caregivers.18 In every situation in which nonadherence was suspected, home health nurse referrals were made in an attempt to provide ongoing education in the child's home and assist in identifying needs of the family members including the primary caregivers. It was not possible in our region to provide DOT strategies on a regular basis at home; however, brief hospitalizations for DOT in every instance were educational and supportive in nature rather than punitive.
Medication adherence is fundamental to successful antiretroviral therapy. Studies of both children and adults clearly demonstrate that adherence is a major factor determining the degree of viral suppression achieved in response to antiretroviral therapy.20,21 Poor adherence often leads to virologic failure. Subtherapeutic antiretroviral drug levels resulting from poor adherence may enhance the development of resistance to 
1 antiretroviral agents in a given regimen and possible cross-resistance to other medications in the same class. Therefore, suboptimal adherence has implications for limiting future effective drug regimens for patients who develop drug-resistant viral strains. Because children face a greater number of years on therapy than adults, when therapy can no longer be delayed because of risk of progression to AIDS, it is extremely important that adherence to the drug regimen is followed. We have 10 patients of 25 that have been maintained for an average of 8 years (range: 4–11 years) on 1 or 2 HAART regimens, with low viral loads (<3 log10 HIV RNA copies per mL), and 4 of these patients have maintained HIV RNA levels below detection (<1.7 log10 HIV RNA copies per mL) for an average of 5 years. Regimens were changed in these patients only because newer regimens with potentially fewer acute and/or chronic adverse effects became available over time. These patients have all maintained normal CD4+ T cell percentages over the years, placing them at extremely low risk for disease progression or death. The caregivers of these patients report almost perfect (>95%) adherence with prescribed HAART for their children.
We support the statement by the American Academy of Pediatrics that "all children deserve effective medical treatment that is likely to prevent substantial harm or suffering or death."22 The specialized medical personnel that serves in the Arkansas Children's Hospital pediatric HIV clinic have >15 years of experience each in the care of children with HIV. Over the years we have witnessed a wonderful improvement in the prognosis of HIV-infected children who were referred to our clinic as effective treatment regimens have become available. From 1988 to 1996, 16 patients died from HIV-related disease that were cared for by our team. We have not observed any deaths in HIV-infected children since 1997. Since the late 1980s, an average of 25 perinatally HIV-infected children have been cared for in the pediatric HIV clinic at Arkansas Children's Hospital, with many being monitored for extended periods.18 Over a 20-year period, only 6 of our patients exhibited high viral loads despite the caregivers' insistence that medications were being administered regularly. It was these 6 children for whom we conducted more intensive strategies in a stepwise approach to ensure adherence, strategies that Crowe et al refer to as "coercion." Step 1 entailed providing a home health nurse referral, step 2 was a 4-day hospitalization for DOT followed by a clinic visit and education of the caregivers regarding the response to therapy, and step 3 entailed submitting a physician-initiated medical neglect report. In 4 of the 6 patients, step 2 resulted in caregiver adherence and favorable clinical and immunologic responses in the patients who have been sustained for many years. In only 2 of our patients was step 3 followed, and in both of these instances court authorities recommended foster care placement for the children because of evidence of medical neglect of the child by the caregiver.18 Both of these children have benefited medically from foster care placement as detailed above. Thus, this stepwise approach was rarely necessary, but in every instance in which it was required, the child has benefited.
Patient 1 is an example of a child who we feel would have died if we had not taken an interventionist approach. Despite the caregiver's insistence of adherence with therapy, this patient had a median CD4+ T cell percentage of 1% before hospitalization for DOT, was wheelchair and home bound, and had severe growth delay and signs and symptoms of heart failure. After 2 hospitalizations for DOT and education of the caregivers regarding evidence for medical neglect of their child, the caregivers obviously began administering therapy, as evidenced by significantly decreased HIV RNA levels and a steady rise in the patient's CD4+ T cell percentage, which increased to a median of 22% in the time period after DOT. The child's growth parameters have changed from <<5% and <<5% for weight and height, respectively, to >25% and approaching 5%, and the child now attends school and walks with a walker. The question remains: Would this child's clinical status be improved today if we had intervened earlier?
Thus, based on extensive medical literature and our own experience over many years of caring for children with HIV, we respectfully disagree with Crowe et al that "[t]here is simply no firm evidence that children will live longer when medicated earlier with AIDS drugs." Because failure to adhere to the HIV treatment regimen is life threatening, we believe it should be considered medical neglect. In the state of Arkansas, it is a criminal offense for medical personnel to fail to report neglect when there is reasonable cause to suspect that it has occurred.23 Because strong evidence exists for life-saving benefits of HAART, it is theoretically possible that a pediatric patient who survives to an age at which they understand the ramifications of nonadherence may eventually seek retribution from medical personnel who ignored evidence for nonadherence by the primary caregivers caring for that child during infancy and early childhood.
REFERENCES
12-12-503, 12-12-507. 2004Related articles in Pediatrics:
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